Risk Measurement of Perinatal and Neonatal Morbidity Characteristics and Applicability of GAIA Case Definitions: Results and Lessons Learnt of a Hospital-Based Prospective Cohort Study in the Valencia Region (2019-2020).

Post-marketing safety surveillance of new vaccines aimed to be administered during pregnancy is crucial to orchestrate efficient adverse events evaluation. This is of special relevance in the current landscape of new vaccines being introduced in the pregnant women population, and particularly due to the recent administration of COVID-19 vaccines in pregnant women. This multi-center prospective cohort study, nested within the WHO-Global Vaccine Safety-MCC study, involved two hospitals in the Valencia region. Hereby, the incidence rates of seven perinatal and neonatal outcomes in the Valencia region are presented. The pooled data analysis of the two Valencian hospitals allowed the estimation of incidence rates in the Valencia Region (per 1000 live births): 86.7 for low birth weight, 78.2 for preterm birth, 58.8 for small for gestational age, 13 for congenital microcephaly, 0.4 for stillbirth, 1.2 for neonatal death and 6.5 for neonatal infection. These figures are in line with what is expected from a high-income country and the previously reported rates for Spain and Europe, except for the significantly increased rate for congenital microcephaly. Regarding the data for maternal immunization, the vaccination status was collected for 94.4% of the screened pregnant women, highlighting the high quality of the Valencian Vaccine Registry. The study also assessed the Valencian hospitals' capacity for identifying and collecting data on maternal immunization status, as well as the applicability of the GAIA definitions to the identified outcomes.

Early-onset sepsis: a cohort study comparing serial clinical observation with laboratory testing.

OBJECTIVE: Early onset sepsis (EOS) remains a serious and potentially fatal illness. We aimed to demonstrate that serial clinical observation (SCO) is a feasible strategy associated with fewer laboratory evaluations and unnecessary antibiotic use. STUDY DESIGN: We compared the admissions and antibiotic therapy in neonates ≥35 weeks' gestation at risk for EOS in a prospective cohort after the implementation of a new protocol based on SCO (n = 381) with a historical cohort which received laboratory testing (n = 417). RESULTS: There was a significant reduction in admissions for suspected sepsis (7.2% vs 2.9%, p = 0.006) and the use of antibiotics (6.1% vs 0.7%, p = 0.000) in the cohort based on SCO. There was no delay in diagnosis. CONCLUSIONS: SCO in neonates ≥35 weeks' gestation at risk for EOS, including chorioamnionitis-exposed infants, is a feasible measure that reduces laboratory evaluations and the overuse of antibiotics respecting the bonding mother-infant.

The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound quinoline. These economical compounds have been used as antimalarial agents for many years. Currently, they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and antiphospholipid antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV- 2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2) inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus, evidence has shown that these structures are leading molecules that can be modified or combined with other therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and HCQ in the immune system, and the use of these antimalarial drugs on diseases.

Total and biologically active CD154 in patients with SLE.

CD154, a member of the tumor necrosis factor receptor family, is involved in several biological responses. In the sera of systemic lupus erythematosus (SLE) patients, the levels of sCD154 have been shown to be increased, however, few reports have dealt with the biologically active tetramer. Here, we assessed the biological activity of the serum CD154 tetramer using bioassays for BC activation and production nitrite or peroxide. The patients showed a markedly increased total sCD154 serum concentration (12.5 +/- 8.2 vs. 3.9 +/- 1.2 ng/ml; p < 0.001). ba-sCD154 was significantly increased in non-treated patients (7.4 +/- 3.4 ng/ml, n = 22; p < 0.001) and patients with the highest SLE disease activity index (SLEDAI) scores (5.3 +/- 2.9 ng/ml, n = 8), but not in stable patients (1.3 +/- 1.2 ng/ml, n = 30) whose values were similar to normal healthy donors (NHD; 0.8 +/- 0.2 ng/ml). Patients with SLEDAI above 8 that recovered after successful treatment displayed significantly decreased levels of ba-sCD154. We conclude that the bioassay is a useful tool discriminating active and stable SLE, as well as non-treated patients.

Decreased transcription, expression and function of low-density lipoprotein receptor in leukocytes from patients with systemic lupus erythematosus.

The low-density lipoprotein receptor (LDLR) is directly involved in the metabolism of low-density lipoprotein (LDL) and its impairment causes accumulation of plasmatic LDL leading to atherosclerosis, a prevalent disease in patients with systemic lupus erythematosus (SLE). We studied LDLR transcription, expression and function in leukocytes patients with SLE and normal healthy donors (NHD). The ratio LDLR/glyceraldehyde-3-phosphate dehydrogenase (GADPH) mRNAs the expression of LDLR and the uptake of LDL-DiI were significantly lower (p < 0.001) in the patients with SLE. On the contrary, patients with SLE had significantly higher (p < 0.0001) levels of total cholesterol, LDL cholesterol and anti-oxLDL autoantibodies (AAb) as compared to NHD. No correlation between LDLR transcription, expression and function with the SLE disease activity index or with treatment was found. The decreased function of LDLR was independent of treatment. It seems dependent on the sterol regulatory binding protein and may be responsible for the increase of plasma LDL cholesterol and oxLDL AAb further increasing the risk of vascular diseases.

Serum adipokine levels in patients with systemic lupus erythematosus.

In patients with systemic lupus erythematosus (SLE) metabolic alterations are often observed, which may be due to either the disease, the genetic background or the treatment. We studied the serum levels of the adipokines leptin, adiponectin, resistin, visfatin and ghrelin in patients with SLE and controls. Leptin levels were lower and adiponectin, ghrelin and visfatin levels were higher in the patients. No significant differences were encountered for resistin. The values of adipokines were independent of treatment, even after correction for body mass index. Inverse correlations were found among leptin and adiponectin, ghrelin and visfatin. We conclude that adipokines are involved in the metabolic imbalance of patients with SLE.

Immunophenotype characteristics of peripheral blood mononuclear leukocytes of chronic idiopathic urticaria patients.

The pathogenesis of chronic idiopathic urticaria (CIU) is not completely understood although autoimmunity has been proposed. The aim of the study was to assess the expression of different leukocyte antigens, by flow cytometry, assaying total blood of 29 patients with CIU and of 20 sex and age matched controls. Moreover, we assessed soluble CD154 a marker of immune cell activation, predominantly memory T cells. When patients were divided depending an their response to the autologous serum skin test (ASST), three different groups were encountered: group 1 (n=11): with negative ASST-, group 2 (n=11): positive ASST (ASST+) with normal lymphocyte counts and group 3 (n=7): ASST+ with low lymphocyte counts (< 1500 cells/mm3). A significant increase in CD19+ percentage and not in the absolute count (P < 0.05) was observed in group 1 as compared to controls and to the other groups. In contrast, CD30+, CD45RO+ and CD4+/CD45RO+ percentages and biologically active soluble CD154 levels were significantly higher (P < 0.05) in group 3 as compared to group 1 or to controls. In ASST positive groups, CD45RO+ and CD4+/CD45RO+ positiveness correlates with wheal diameter. In conclusion, memory cells may play a role in these different types of patients and in understanding CIU pathogenesis.

Immunophenotype characteristics of peripheral blood mononuclear leukocytes of chronic idiopathic urticaria patients

La patogénesis de la urticaria crónica idiopática (CIU) no se conoce completamente; sin embargo, la autoinmunidad juega un papel importante en un subgrupo de pacientes. El objetivo de este estudio fue la determinación de antígenos leucocitarios en sangre total, utilizando citometría de flujo, de 29 pacientes con CIU y 20 controles de similar edad y sexo. Adicionalmente, se determinó el CD154 soluble como marcador de activación de células inmunes, predominantemente linfocitos T de memoria. Se describieron 3 grupos de pacientes de acuerdo al resultado de la prueba de suero antólogo (ASST): grupo 1: negativo (n = 11), grupo 2: prueba positiva y contaje linfocitario normal (n = 11) y grupo 3 prueba positiva y contaje linfocitario bajo (< 1500 células/mm3) (n = 7). En el grupo 1, se observó un aumento significativo (P < 0,05) en el porcentaje de células CD19+ aunque no en su número absoluto cuando se comparó con los controles y los pacientes con ASST +. En contrapartida, el porcentaje de células positivas para CD30, CD45RO y CD4/CD45RO y los niveles de CD154 soluble biológicamente activo fueron significativamente mayores (P < 0,05) en el grupo 3, en comparación con los controles y el grupo 1. Además, en los grupos con ASST positiva, los porcentajes de células CD45RO+ y CD4/CD45RO+ se correlacionan con el tamaño del habón a la ASST. En conclusión, las células de memoria pudieran jugar un papel importante en la patogénesis de la CIU.

Presencia de agentes antígenos extractables del núcleo en niños con hepatitis autoinmune / Presence of extractable antigens of the nucleus in children with autoimmune hepatitis

La hepatitis autoinmune (HAI) es una enfermedad inflamatoria del hígado, con autoanticuerpos tisulares, altos niveles de inmunoglobulina IgG, ausencia de etiología conocida y con respuesta a la terapia inmunosupresora. Los anticuerpos han sido intensamente evaluados y conducen a la clasificación de HAI en tres grupos serológicos. El 20 por ciento de niños con HAI muestran antígenos extractables del núcleo (anti Sm, anti SSA y anti SSB) sin que estos pacientes muestren criterios para otras enfermedades autoinmunes. Se reporta un caso de un adolescente masculino de 12 años de edad quién presentó clínica de esplenomegalia, insuficiencia renal aguda secundaria a nefritis intersticial, elevación transaminasas, hipergammaglobulinemia, hipocomplementemia, ANA y anti DNA positivos, anti Sm y anti SSA positivos, anticardiolipinas IgM e IgG positivas, SMA positivo y biopsia hapática con hallazgos histopatológicos compatibles con hepatitis autoinmune. A pesar de presentar anticuerpos altamente específicos para otras enfermedades autoinmunes (Ejm. LES) el paciente no cumple los criterios mínimos establecidos

Total and biologically active serum-soluble CD154 in patients with chronic idiopathic urticaria.

The pathogenesis of chronic idiopathic urticaria (CIU) is not understood completely; however, autoimmunity has been implicated. Because membrane and soluble forms of CD154 have been reported to be increased, in several autoimmune diseases, we have quantified the soluble CD154 (sCD154) molecule by a sandwich enzyme-linked immunosorbent assay in serum samples of 32 patients with CIU (aged 32 +/- 12 years) and compared them with 32 age- and sex-matched nonallergic controls. A marked increase was observed in patients with CIU as compared with controls (4.8 +/- 2.6 ng/mL versus 2.9 +/- 0.9 ng/mL; p < 0.0005). No significant differences were found between groups of patients with positive or negative autologous serum skin test. A biological assay to determine sCD154 showed that patients with positive autologous serum skin test have the highest levels (4.9 +/- 1.2 ng/mL) of biologically active sCD154 as compared with their negative counterparts (2.2 +/- 1.3 ng/mL; p < .001) and controls (0.6 +/- 0.3 ng/mL; p < 0.001). Active sCD154 can be derived from mast cell activation or other leukocytes. It is concluded that active sCD154 may be involved in the immune activation observed in patients with CIU.

Determinación de alfa feto proteina en pacientes infectados con virus B y C comunicación preliminar / Serum alpha protein in patients infected whit hepatitiis B and C vitus

La presencia de niveles detectantes de Alfa Feto proteina (aFP), fue investigada mediante radio inmuno ensayo (RIA), en setenta y ocho sueros clasificados como sigue: Treinta y dos sueros de donantes voluntarios (Grupo A), quince sueros positivos para anticuerpos Anti VHC, diez y nueve sueros de portadores del virus VHB (Grupo B), y doce sueros de un grupo de individuos con solo Anticore positivo (Grupo C). Niveles superiores al rango máximo calculado de AFP, (mayores de 2,6 ng/ml) fueron detetados en dos individuos del Grupo A, en dos sueros VHC positivos, y en seis portadores del virus VHB. Ningún suero del grupo C demostró elevación de los valores aFP. Dos de los sueros B positivos con actividad aumentada de aFP presentaron valores significativamente elevados de esta proteina, 13 y 20 veces superiores al límite. En Venezuela, los niveles de aFP en el portador crónico del VHB no parecen ser comparables a los reportados en países hiperendémicos para este virus por lo cual su deteción debe ser interpretada con precaución. La necesidad de analizar los rangos reales de aFP en grupos poblacinales normales es establecida

Hepatitis C en Venezuela: comunicación preliminar / Hepatitis C in Venezuela: preliminary comunication

Quinientas muestras de suero de donantes voluntarios de Banco de Sangre fueron investigadas para determinar la presencia de anticuerpos anti-VHC mediante un método inmunoenzimático de reciente desarrollo a nivel mundial. La prevalencia de muestras verdaderamente positivas fue de 1.2% (6/500), 2 veces superior a la reportada en la gran mayoría de los países industrializados. De estos 6 sueros positivos, uno (16.6%) mostró reactividad simultánea de anticuerpos anticore del VHB. De 12 sueros provenientes de pacientes con diagnóstico de hepatitis No A No B (25%) resultaron reactivos para anticuerpos anti-VHC mientras de 32 sueros con pesquisa inmunodiagnóstica negativa para VHA y VHB, 4(12.5%) mostraron anticuerpos anti-VHC. Dos muestras (12.5%) de 16 sueros persistentemente anticore positivos demostraron presencia de anticuerpos anti-VHC resultando este último indetectable en 2 casos de hepatitis crónica autoinmune. Nuestros resultados indican que en Venezuela la VHC constituye un problema significativo de salud pública coexistente en algunos casos con infección por VHB

Evaluacion de un ensayo de hibridizacion molecular para la deteccion de ADN circulante del virus de hepatitis B: correlacion inmunoclinica / Evaluation of a molecular hyBridization trial for the detection of circulating DNA of hepatitis B virus: immunoclinical correlation

Correlación inmunoclínica del ADN viral circulante del VHB fue realizada utilizando para su detección la técnica de hibridización en fasefluída y una sonda de ADN complementario marcada con I125 (Abbott-Genostics TM). La correlación se practicó en 12 sueros incluyendo 8 de portadores comprobados del VHB con o sin enfermedad hepática. Sólo los sueros sin enfermedad hepática. Sólo los sueros AgeHB positivos demostraron presencia de ADN viral circulante en rangos de 60 a 2800 pcg/ml. El ensayo resultó de relativo fácil manejo; sin embargo el alto costo y el uso de un radioisótopo de vida media corta limita su uso rutinario, encontrándose aún bajo investigación su aplicabilidade clínica. Se discute la significancia inmunopatológica de los hallazgos

Diarrea crónica como expresión clínica de la hipogammaglobulinemia común variable. A propósito de tres casos / Chronic diarrhoea in common variable hypogammaglobulinemia: report of 3 cases

La diarrea crónica puede manifestarse hasta en un 60% de los pacientes que presentan compromiso del compartimiento inmunológico humoral, específicamente en la hipogammaglobulinemia común variable (HCV). Presentamos 3 casos con HCV de aparición tardía, en quienes la diarrea crónica fue el síntoma cardinal del cuadro clínico. Los estudios inmunodiagnósticos revelaron niveles no cuantificables o subnormales tanto de Inmunoglobulina G como de M y A, con complemento hemolítico total preservado, y pantalla autoinmune negativa. La exploración del compartimiento celular demostró elevado número de linfocitos T supresores (CD8) con hiporespuesta de la población linfocitaria total frente a mitógenos policionales tipo PHA. El abordaje clínico de los pacientes con HCV debe ser practicado por un equipo multiespecializado conformado por el inmunólogo clínico, el gastroenterólogo y el infectólogo.